Proliferation and differentiation in tissue are modulated by interactions between extracellular and intracellular molecules. Extracellular signals, such as the cytokine tumor necrosis factor-.alpha., are telegraphed as molecular transpositions through the plasma membrane via trans- orjuxtamembrame proteins to target intracellular components. In many cases, the target components comprise second messenger pathways which may regulate transcription rates of tissue-specific genes. Transcription rates are controlled by the interaction between second messenger pathway components, transcription factors, RNA polymerase(s), and regulatory elements (promoter) of the gene(s).
Transcription factors bind to canonical DNA sequences present within the gene promoter and thus alter the conformation of the DNA or alter the affinity of the DNA for other cofactors or the transcription initiation complex. Many transcription factors are tissue-specific or cell-type specific, but others also appear to be present in all tissues. Yet other transcription factors are present in well-defined groups of organs, such as those involved in neurogenesis, myogenesis, or hematopoiesis (Reichmann, V. and Sablitzky, F. (1995) Cell Growth Differ. 6:837-843).
Nuclear factor kappa B (NF.kappa.B/Rel) is a critical transcription factor for maximal expression of many cytokines that are involved in the pathogenesis of inflammatory diseases. Activation of NF.kappa.B/Rel initiates both extracellular and intracellular regulatory events that result in autoregulation of the inflammatory cascade through modulation of NF.kappa.B/Rel activation (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell. Mol. Biol. 17:3-9). NF.kappa.B/Rel is active in glial and neuronal cells during neurogensis and might also be important for viral replication in the central nervous system (O'Neill, L. A. and Kaltschmidt, C. (1997) Trends Neurosci. 20:252-258).
The DNA-binding forms of the NF.kappa.B/Rel family of proteins are under the control of an inhibitory family of proteins, I.kappa.B. The I.kappa.B proteins maintain NF.kappa.B/Rels in an inactive state in the cytoplasm. Chronic downregulation of I.kappa.B proteins in smooth muscle cells has been linked to atherosclerosis (Bourcier, T. et al. (1997) J. Biol. Chem. 272:15817-15824). Inhibition of NF.kappa.B activation produces significant anti-inflammatory activity which may be mediated by the inhibition of transcription of certain pro-inflammatory mediators and adhesion molecules (Jourd'heuil, D. et al. (1997) Keio J. Med. 46:10-15).
Cardiomyopathy (CM) is a heart muscle disease of unknown cause in which significant hypertrophy has been documented. The molecular mechanism for the development of hypertrophic CM is not well understood. An animal model of hypertrophic CM, the spontaneously hypertensive rat (SHR), has been developed and a protein, myotrophin, has been isolated from the myocardium of SHR heart. Rat myotrophin stimulates protein synthesis in rat myocytes in vitro (Sen, S. et al. (1990) J. Biol. Chem. 265:16635-16643). Furthermore, myotrophin contains two half and two complete ankyrin repeats (18, 33, 33, and 14 residues) that are highly homologous to those present within I.kappa.B alpha. Myotrophin formed ternary complexes with subunits of NF.kappa.B/Rel and a K.kappa. DNA probe and the authors suggested that the NF.kappa.B/Rel complex is a specific target for myotrophin (Sivasubramanian, N. et al. (1996) J. Biol. Chem. 271:2812-1816).
Rat myotrophin is identical to a protein isolated from rat cerebellum, V-1. The V-1 protein was determined to be related to cell cycle control and cell fate determination proteins. Taoka, M. et al. also suggested that V-1 protein could be used in the diagnosis or treatment of hereditary nervous disease (1994; J. Biol. Chem. 269:9946-9951; Mitsubishi Kasei Corp., J04193899-A). A similar protein has been isolated from human cardiomyopathic heart, but the DNA coding sequence was not reported (Sil, P. et al. (1993) Circ. Res. 73:98-108).
The discovery of a new human myotrophin and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of myopathic, neuronal, immunological, and neoplastic disorders.